Eligibility Criteria

Group A inclusion/exclusion

Inclusion Criteria:

1. Age 18-65

2. Written informed consent

3. Meets DSM-IV criteria (by Structured Clinical Interview for DSM-IV - SCID-I/P) for
MDD, current

4. Inventory of Depressive Symptomatology - Self-Rated (IDS-SR30) score of > 24 at
screening, baseline and start of double-blind phase (Phase 2)

5. May have a history of failure to respond to up to two FDA-approved antidepressants at
adequate doses during the current episode for at least 8 weeks, and for inclusion
into the Phase 2 subjects must have failed the 8-week prospective citalopram
treatment.

6. Montgomery Asberg Depression Rating Scale (MADRS) score of 18 or higher at baseline
and start of Phase 2.

Exclusion Criteria:

1. Pregnant women or women of child bearing potential who are not using a medically
accepted means of contraception (to include oral contraceptive or implant, condom,
diaphragm, spermicide, intrauterine device, tubal ligation, or partner with
vasectomy)

2. Patients who no longer meet DSM-IV criteria for MDD during the baseline visit

3. Patients who demonstrate > 50% decrease in depressive symptoms as reflected by the
IDS-SR total score from screen to baseline

4. Serious suicide or homicide risk, as assessed by evaluating clinician A serious
suicide risk will be considered an inability to control suicide attempts, imminent
risk of suicide in the investigator's judgment, or a history of serious suicidal
behavior, which is defined using the Columbia-Suicide Severity Rating Scale (C-SSRS)
as either (1) one or more actual suicide attempts in the 3 years before study entry
with the lethality rated at 3 or higher, or (2) one or more interrupted suicide
attempts with a potential lethality judged to result in serious injury or death.

5. Unstable medical illness including cardiovascular, hepatic, renal, respiratory,
endocrine, neurological, or hematological disease

6. The following DSM-IV diagnoses: substance use disorders active within the last six
months, any bipolar disorder (current or past), any psychotic disorder (current or
past)

7. History of a seizure disorder or clinical evidence of untreated hypothyroidism

8. Patients requiring excluded medications (see Table 3 for details)

9. Psychotic features in the current episode or a history of psychotic features, as
assessed by SCID

10. Any investigational psychotropic drug within the last 3 months

11. Have failed 3 or more adequate antidepressant trials during the current Major
Depressive Episode by MGH-ATRQ criteria.

12. Patients with a history of antidepressant-induced hypomania.

13. Patients with any evidence of clinically significant liver abnormalities, or any
liver transaminase level >1.5 X ULN at initial screening, or >5 x ULN during Phase 2
treatment.

14. Axis II personality disorders that are the primary purpose of treatment, or would
interfere with a patient's safety or compliance.

15. Patients currently being treated for a respiratory disorder (including asthma or
COPD)

16. Any subject who scores a 5 or higher on item #10 of the MADRS

Group B inclusion/exclusion

Inclusion criteria:

1. Age 18-65

2. Written informed consent

3. Meets DSM-IV criteria (by Structured Clinical Interview for DSM-IV - SCID-I/P) for
MDD, current

4. Inventory of Depressive Symptomatology - Self-Rated (IDS-SR30) score of > 24 at
screening and baseline visits, that is at the start of Phase 2

5. Has a history of failure to respond to 1, 2, or 3 FDA-approved antidepressants at
adequate doses during the current episode for at least 8 weeks, as defined by the MGH
Antidepressant Treatment Response Questionnaire (MGH-ATRQ), and must be currently on
the failed SSRI for at least 8 weeks and on a stable dose for at least 4 weeks.

6. Montgomery Asberg Depression Rating Scale (MADRS) score of 18 or higher at baseline
and start of Phase 2.

Exclusion Criteria

1. Pregnant women or women of child bearing potential who are not using a medically
accepted means of contraception (to include oral contraceptive or implant, condom,
diaphragm, spermicide, intrauterine device, tubal ligation, or partner with
vasectomy)

2. Patients who no longer meet DSM-IV criteria for MDD during the baseline visit

3. Serious suicide or homicide risk, as assessed by evaluating clinician A serious
suicide risk will be considered an inability to control suicide attempts, imminent
risk of suicide in the investigator's judgment, or a history of serious suicidal
behavior, which is defined using the Columbia-Suicide Severity Rating Scale (C-SSRS)
as either (1) one or more actual suicide attempts in the 3 years before study entry
with the lethality rated at 3 or higher, or (2) one or more interrupted suicide
attempts with a potential lethality judged to result in serious injury or death.

4. Unstable medical illness including cardiovascular, hepatic, renal, respiratory,
endocrine, neurological, or hematological disease

5. The following DSM-IV diagnoses: substance use disorders active within the last six
months, any bipolar disorder (current or past), any psychotic disorder (current or
past)

6. History of a seizure disorder or clinical evidence of untreated hypothyroidism;

7. Patients requiring excluded medications (see Table 3 for details)

8. Psychotic features in the current episode or a history of psychotic features, as
assessed by SCID

9. Any investigational psychotropic drug within the last 3 months

10. Have failed 3 or more adequate antidepressant trials during the current Major
Depressive Episode by MGH-ATRQ criteria.

11. Patients with a history of antidepressant-induced hypomania.

12. Patients with any evidence of clinically significant liver abnormalities, or any
liver transaminase level >2 X ULN at initial screening, or >5 x ULN during Phase 2
treatment.

13. Axis II personality disorders that are the primary purpose of treatment, or would
interfere with a patients safety or compliance.

14. Patients currently being treated for a respiratory disorder (including asthma or
COPD)

15. Any subject who scores a 5 or higher on item #10 of the MADRS